Synthetic organic chemistry plays a key role in translating the discoveries from human genomics into deep biological understandings and into new and effective therapies. Genome biology has developed new tools for dissecting the genome and is shining an increasingly bright light on genome sequences, including the variation in sequences among members of the human population and its relationship to an individual's susceptibility to specific diseases. The next step is clear yet daunting - how do we exploit these advances to gain deep insights into human physiology and pathophysiology and to discover effective treatments for the major human diseases? Lay language statement: The ability to synthesize optimal small-molecule screening collections, ones that anticipate each of the phases in which chemistry plays a role in achieving the above goal, will greatly facilitate our ability to identify, optimize and manufacture small-molecule drugs that can be used to treat human disease. We plan to advance synthetic organic chemistry in ways that will allow these goals to be achieved by combining innovation and execution. We intend to innovate around a powerful three-phase strategy (build/couple/pair) in diversity-oriented small-molecule synthesis that emanates from our CMLD community and that may have the potential to achieve the above goals. We will ensure that innovative chemical methodology, especially methods based on powerful catalysts that impart high levels of stereochemical control on reactants, is coupled directly to our strategy for library development. We will innovate in computational chemical biology to provide analysis tools that guide the use of synthetic methodology towards the target optimal screening collections. Using this approach, we feel that our CMLD community will continue to be more than the sum of its parts. This organization and synthesis strategy will together drive our activities throughout our renewal phase. We intend to execute on this plan in part by establishing a strong collaboration with the Broad Institute's team of senior, professional staff chemists. These chemists have established a diversity synthesis Production Facility and an electronic data pipeline that we intend to use in order to achieve the scaled synthesis of compounds emanating from the proposed pathways efficiently and effectively. We are strongly committed to use the innovation of the CMLD synthetic and computational chemistry to drive an implementation activity that will yield substantial quantities of pure and highly novel compounds for small molecule screening on a wide scale, and thereby to facilitate the discovery of new medicines in the future.